The predominant polymicrobic infection of mankind is expressed clinically as periodontal disease, which afflicts nearly 1/2 of the population by 50 years of age, and is related to development of a microbial biofilm colonizing the supra- and subgingival sulcus. The suggested mechanisms of pathogenesis are varied, in most part due to the complex microbial community consisting of numerous bacterial taxa, viruses, and fungi. Nevertheless, certain of these subgingival microbial consortia are consistently correlated with a progressive destruction of soft and hard tissue that has been well documented to occur in clinical settings (i.e.periodontitis). Molecular microbiologic studies have described nearly 500 species of bacteria that can inhabit this ecololgical niche. A predominant pathogenic consortium identified in a majority of adult periodontitis patients consists of P. gingivalis, T. forsythensis, and T. denticola. The correlation of this consortium with disease has been proposed to result from synergistic physiological, host evasion, and/or tissue destructive capabilities among the component species. Similarly, bacterial consortia identified in health as "early biofilm colonizers" (eg. S. gordonii, A. naeslundii, V. atypical) and "bridging species" (eg. F. nucleatum, C. ochraceae, P. loescheii) have been identified to be crucial in establishment of a pathogenic biofilm. The objectives of this R01 application are to test an hypothesis that a "pathogenic polybacterial consortium" comprises a "virulence web" that uniquely synergizes to increase tissue destructive host responses, and that host immune responses are modified by the consortium to be less effective. Four specific aims are proposed using an animal model system to test this hypothesis: (1) To determine molecular interbacterial synergistic virulence effects of a pathogenic consortium P. gingivalis, T. forsythensis, and T. denticola in an in vivo calvarial bone resorption model, (2) To determine the characteristics of acquired immune responses to a polybacterial infection and the ability of this response to modulate transcriptome & bone resorption responses, (3) To determine the characteristics of active immune responses to polybacterial immunization and the ability of this response to modulate transcriptome & bone resorption responses, and (4) To determine virulence effects of eommensal oral bacteria, S. gordonii, A. naeslundii, V. atypica, F. nucleatum, C. ochracea, and P. loescheii, in an in vivo calvarial bone resorption model. The long-range goals are to document transcriptome responses to pathogenicand commensal potybacterial challenges, virulence synergisms, characterize acquired and active immune responses, and relate these to tissue loss and bone resorption. The significance of this grant is to understand the host-bacterial interactions that occur in the oral cavity. The net result of these interactions have been suggested by clinical observations to have an effect on systemic diseases and their sequelae. Consequently, the host response to the chronic infections must be considered as critical in modulating infection and maintaining general health.